Phase 2a Trial of Rodatristat Ethyl, Potential Oral PAH Therapy, Begins Dosing
A Phase 2a trial testing the potential oral treatment rodatristat ethyl in patients with pulmonary arterial hypertension (PAH) has begun dosing, its developer announced.
Rodatristat ethyl (or RVT-1201), the lead therapy candidate of Altavant Sciences, is an inhibitor of the enzyme tryptophan hydroxylase. The therapy is designed to block the production of circulating serotonin, a hormone implicated in the tightening and growth of pulmonary artery muscle cells, subsequently narrowing arteries and triggering PAH. (Altavant is part of Roivant Pharma group.)
Besides PAH, excessive levels of serotonin are also found in people with idiopathic pulmonary fibrosis and sarcoidosis. By lowering serotonin levels, scientists believe that rodatristat ethyl – given in an immediate-release tablet formulation — may halt or reverse these diseases.
The double-blind, multi-center study (NCT03924154), named ELEVATE 1, is designed to assess the therapy’s safety, tolerability, pharmacological profile, and ability to bind to its target in adults with PAH. Exploratory efficacy measures, including exercise capacity, breathlessness, and World Health Organization functional class, will also be analyzed.
Up to 36 PAH patients, ages 18 to 75, will be recruited at nearly 20 centers across the U.S. and Canada. Enrollment is ongoing at six U.S. locations; more information on sites and contacts can be found here.
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To join the 12-week trial, participants are required to undergo a six-minute walk distance test to assess exercise capacity, and to be taking PAH medications for at least three months. These can include endothelin receptor antagonists, phosphodiesterase inhibitors, and Adempas (riociguat, marketed by Bayer).
Due to rodatristat ethyl’s complementary mechanism of action relative to existing medications, those enrolled will be allowed to continue on their current treatments, Altavant said in a press release.
Following a four-week screening period, patients will be randomized 2:1 to either rodatristat ethyl or placebo, both given twice daily along with food for six weeks. They will then be followed for another two weeks.
The trial is expected to be completed by February 2020, and data collected will be used to inform a Phase 2b efficacy study.
“Initiating the ELEVATE 1 Study is a significant milestone for Altavant, and represents our commitment to the rare respiratory disease community, and our approach to patient-centric, transparent clinical development,” William T. Symonds, PharmD, Altavant’s CEO, said in the release.
“Rodatristat ethyl is a first-in-class investigational medicine for the treatment of PAH,” Symonds said, adding that the trial’s goal is to provide evidence of the therapy’s mechanism in PAH, “which we believe could halt or reverse the pulmonary vascular remodeling characteristic of the disease. Success in this study would take us one step closer to being able to provide a much-needed, new therapeutic option to PAH patients.”
Marc Humbert, MD, PhD, a professor of respiratory medicine at Université Paris-Saclay, and director of the French National Reference Centre for Pulmonary Hypertension, added: “while the introduction of vasodilators was a significant advancement in treating PAH … there is still a need to develop novel treatment options to further improve lifespan.”
Humbert, who is also a member of Altavant’s scientific advisory board, emphasized that “new R&D efforts … may ultimately give us an opportunity to offer a new treatment option to PAH patients that provides better outcomes.”
In line with evidence from healthy volunteers, preclinical results presented this year at the 13th Annual World Congress on Pulmonary Vascular Disease in Barcelona indicated that the median effective dose of rodatristat ethyl lowered serotonin production by about 50%. This led to a reduction of pulmonary artery wall thickness in rats.
Preliminary results from a study in healthy volunteers demonstrated dose-proportional increases in exposure following administration of rodatristat ethyl. All tested doses and regimens were generally well-tolerated.